US6232476B1 - Intermediates in a process for cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine - Google Patents
Intermediates in a process for cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine Download PDFInfo
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- US6232476B1 US6232476B1 US09/575,310 US57531000A US6232476B1 US 6232476 B1 US6232476 B1 US 6232476B1 US 57531000 A US57531000 A US 57531000A US 6232476 B1 US6232476 B1 US 6232476B1
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- 0 *C.C[Ar] Chemical compound *C.C[Ar] 0.000 description 3
- PXJRBMPBZDCTQH-UHFFFAOYSA-N C.COCCN1CCCC1 Chemical compound C.COCCN1CCCC1 PXJRBMPBZDCTQH-UHFFFAOYSA-N 0.000 description 1
- PWSVSWQCAZFFON-UHFFFAOYSA-N C1=CC=C(C2=C(C3=CC=CC=C3)C3=C(C=CC=C3)CC2)C=C1.CC.CC(C)C Chemical compound C1=CC=C(C2=C(C3=CC=CC=C3)C3=C(C=CC=C3)CC2)C=C1.CC.CC(C)C PWSVSWQCAZFFON-UHFFFAOYSA-N 0.000 description 1
- KXJPEKNOTUSHSS-UHFFFAOYSA-N CC(=O)CC(=O)C1=CC=CC=C1.CC1=CC=C(C(=O)Cl)C=C1.CC1=CC=C(C(=O)O)C=C1.COC1=CC=C(Br)C(C)=C1.COC1=CC=C(Br)C(CBr)=C1.COC1=CC=C(Br)C(CCC(=O)C2=CC=CC=C2)=C1.COC1=CC=C(Br)C(CCC2(C3=CC=CC=C3)OCCO2)=C1.COC1=CC=C(C(=O)C2=CC=C(C)C=C2)C(CCC(=O)C2=CC=CC=C2)=C1.COC1=CC=C(C(=O)C2=CC=C(C)C=C2)C(CCC2(C3=CC=CC=C3)OCCO2)=C1.COC1=CC=C2C(=C1)CCC(C1=CC=CC=C1)=C2C1=CC=C(C)C=C1.COC1=CC=C2C(=C1)CCC(C1=CC=CC=C1)C2C1=CC=C(OCCN2CCCC2)C=C1.C[Cu].O=S(Cl)Cl.OC1=CC=C(C(O)O)C=C1.[C-]#[N+]C1=CC=C(C)C=C1.[C-]#[N+]C1=CC=C(O)C=C1 Chemical compound CC(=O)CC(=O)C1=CC=CC=C1.CC1=CC=C(C(=O)Cl)C=C1.CC1=CC=C(C(=O)O)C=C1.COC1=CC=C(Br)C(C)=C1.COC1=CC=C(Br)C(CBr)=C1.COC1=CC=C(Br)C(CCC(=O)C2=CC=CC=C2)=C1.COC1=CC=C(Br)C(CCC2(C3=CC=CC=C3)OCCO2)=C1.COC1=CC=C(C(=O)C2=CC=C(C)C=C2)C(CCC(=O)C2=CC=CC=C2)=C1.COC1=CC=C(C(=O)C2=CC=C(C)C=C2)C(CCC2(C3=CC=CC=C3)OCCO2)=C1.COC1=CC=C2C(=C1)CCC(C1=CC=CC=C1)=C2C1=CC=C(C)C=C1.COC1=CC=C2C(=C1)CCC(C1=CC=CC=C1)C2C1=CC=C(OCCN2CCCC2)C=C1.C[Cu].O=S(Cl)Cl.OC1=CC=C(C(O)O)C=C1.[C-]#[N+]C1=CC=C(C)C=C1.[C-]#[N+]C1=CC=C(O)C=C1 KXJPEKNOTUSHSS-UHFFFAOYSA-N 0.000 description 1
- CLIWFCHBMVPAJW-UHFFFAOYSA-N CC1=CC=C(C2CCC3=C(C=CC(C)=C3)C2C2=CC=C(C)C=C2)C=C1 Chemical compound CC1=CC=C(C2CCC3=C(C=CC(C)=C3)C2C2=CC=C(C)C=C2)C=C1 CLIWFCHBMVPAJW-UHFFFAOYSA-N 0.000 description 1
- HLNRRPIYRBBHSQ-UHFFFAOYSA-N CCCN1CCCC1 Chemical compound CCCN1CCCC1 HLNRRPIYRBBHSQ-UHFFFAOYSA-N 0.000 description 1
- VGWFYSDJXHPVBC-UHFFFAOYSA-N COC1=CC=C(C2C3=C(C=C(OC)C=C3)CCC2C)C=C1 Chemical compound COC1=CC=C(C2C3=C(C=C(OC)C=C3)CCC2C)C=C1 VGWFYSDJXHPVBC-UHFFFAOYSA-N 0.000 description 1
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/48—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation involving decarboxylation
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- This invention provides an improved process for cis-1- ⁇ 2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl ⁇ pyrrolidine which is an intermediate for the preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol which is useful for the treatment of osteoporosis.
- R 2 is phenyl or cyclopentyl and R 3 is H
- R 1 is H or OCH 3 ;
- R 2 is H, OH, OCH 3 , OPO(OC 2 H 5 ) 2 , OCH 2 CH 2 N(C 2 H 5 ) 2 , OCH 2 COOH or OCH(CH 3 ) COOH.
- Ph is a 1,2-phenylene radical
- Ar is a monocyclic carbocyclic aryl group substituted by tertiary amino-lower alkyl-oxy, in which tertiary amino is separated from oxy by at least two carbon atoms
- R is hydrogen, an aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or a heterocyclic aryl aliphatic radical, the group of the formula —(C n H 2n-2 )—stands for an unbranched alkylene radical having from three to five carbon atoms and carrying the groups Ar and R, salts, N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, as well as procedure for the preparation of such compounds.
- Ph is a 1,2-phenylene radical
- Ar is a monocyclic aryl radical substituted by at least one amino-lower alkyl-oxy group in which the nitrogen atom is separated from the oxygen atom by at least two carbon atoms
- R is an aryl radical
- R 1 and R 2 are selected from the class consisting of lower alkyl and lower alkyl linked together to form a 5 to 7 ring member saturated heterocyclic radical.
- This invention provides intermediate compounds which are useful for the preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol.
- These compounds include: 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one; 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane; 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one; and 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene; and (4-Benzyloxy-phenyl)- ⁇ 4-methoxy-2-[2-(2-phenyl-[1,3]dioxolan-2-yl)-ethyl]-phenyl ⁇ -methanone.
- This invention also provides a method of preparing Cis-1- ⁇ 4-[6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenoxy]ethyl ⁇ pyrrolidine which comprises the following steps:
- step 2 The product of step 1 is used to alkylate benzoyl acetate ethyl ester followed by decarboxylation to provide 3-(2-bromo-5-methoxyphenyl)-1-phenyl-propan-1-one;
- step 2 The product of step 2 is reacted with ethylene glycol to produce 2-[2-(2-bromo-5-methoxyphenyl)-ethyl]-2-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane;
- step 3 undergoes metal-halogen exchange with n-butyl lithium and is reacted with 4-benzyloxy benzonitrile to produce 2-[2-(2-(4-benzyloxybenzoyl)-5-methoxy phenyl)-ethyl]-2-phenyl-[1,3]-dioxolane which is subjected to acid hydrolysis of the 1,3 dioxolane to provide 3-[2-(4-benzyloxybenzoyl)-5-methoxyphenyl]-1-phenyl propan-1-one;
- step 4 The product of step 4 is treated with titanium (III) chloride and zinc-copper couple to produce 4-(4-benzyloxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene;
- step 5 The product of step 5 is hydrogenated and treated with triphenyl phosphine, DEAD and 1-(2-hydroxyethyl)pyrolidine to produce 1- ⁇ 2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)-ethyl ⁇ -pyrolidine.
- This invention also provides a method of reacting
- R is a protected phenol
- This invention provides a new synthesis of cis-1- ⁇ 2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl ⁇ pyrrolidine as shown below.
- protected phenol includes optional benzyloxy groups substituted with alkoxy, nitro or halogen, and other acceptable alcohol protecting groups.
- the synthesis begins with bromination 1 of 2-bromo-5-methoxy-toluene to provide the benzyl bromide 1-Bromo-2-bromomethyl-4-methoxy-benzene.
- Alkylation of ethyl benzoylacetate 2 with the benzyl bromide followed by decarboxylation leads to the ketone 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one, which is protected 3 as the ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane.
- the diketone undergoes a titanium mediated McMurry type coupling 5 to provide the alkene 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene, which possesses the carbon framework of cis-1- ⁇ 2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl ⁇ pyrrolidine with all the functional groups in place.
- a palladium catalyzed hydrogenation achieves the reduction of the olefinic double bond and deprotection of the benzyl ether in one pot.
- N-ethyl-pyrrolidino side-chain is achieved under Mitsunobu conditions to afford 1- ⁇ 2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-phenoxy]-ethyl ⁇ -pyrrolidine, the key precursor to cis-1- ⁇ 2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl ⁇ pyrrolidine.
- This compound is converted to cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol with HBr as described in U.S. Pat. No. 5,552,241.
- the concentrated mixture was subjected to acid hydrolysis and decarboxylation by refluxing for overnight in a solution containing 40 ml of glacial acetic acid, 5 ml of concentrated sulfuric acid, and 10 ml of water.
- the reaction mixture was then neutralized with 10% NaOH and extracted with methylene chloride.
- the extracts were concentrated to give a weight of 19.43 g crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one (yield: 87%). This compound was used in next step without further purification.
- TiCl 3 (2.062 g, 13 mmol) and Zn—Cu couple (2.02 g, 30.8 mmol) were placed in a 200 ml round bottom flask under N2. Anhydrous dimethoxyethane (40 ml) was added and the mixture was refluxed for 1 h.
- the Zn—Cu couple is prepared by adding zinc dust (9.8 g, 150 mmol) to 40 ml of deoxygenated water, purging the slurry with N2 gas for 15 min, and than adding CuSO4 (0.75 g, 4.7 mmol). The black slurry was filtered under N2, washed with deoxygenated H 2 O, acetone, ether, and then stored under N 2 .
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Abstract
This invention provides an improved process for cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine which is an intermediate for the preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol which is useful for the treatment of osteoporosis.
Description
This application is filed claiming priority from Provisional Application No. 60/135,578 filed on May 24, 1999.
1. Field of the Invention
This invention provides an improved process for cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine which is an intermediate for the preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol which is useful for the treatment of osteoporosis.
2. Description of the Related Art
A preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthhalene-2-ol is described in U.S. Pat. No. 5,552,241 which is hereby incorporated by reference. This compound is an estrogen agonist and is useful for treatment of conditions caused by estrogen difficiency. U.S. Pat. No. 5,552,241 also describes the synthesis of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine by hydrogeneration of nafoxidine.
or —CH2CHOHCH2OH.
Bencze, et al., J. Med. Chem., 10, 138 (1967) prepared a series of tetrahydronaphthalenes intended to achieve separation of estrogenic, antifertility and hypocholesterolemic activities. These structures are the general formula
wherein R1 is H or OCH3; R2 is H, OH, OCH3, OPO(OC2H5)2, OCH2CH2N(C2H5)2, OCH2COOH or OCH(CH3) COOH.
U.S. Pat. No. 3,234,090 refers to compounds which have estrogenic and antifungal properties of the formula
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic carbocyclic aryl group substituted by tertiary amino-lower alkyl-oxy, in which tertiary amino is separated from oxy by at least two carbon atoms, R is hydrogen, an aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or a heterocyclic aryl aliphatic radical, the group of the formula —(CnH2n-2)—stands for an unbranched alkylene radical having from three to five carbon atoms and carrying the groups Ar and R, salts, N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, as well as procedure for the preparation of such compounds.
U.S. Pat. No. 3,277,106 refers to basic ethers with estrogenic, hypocholesterolemic and antifertility effects which are of the formula
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic aryl radical substituted by at least one amino-lower alkyl-oxy group in which the nitrogen atom is separated from the oxygen atom by at least two carbon atoms, R is an aryl radical, and the portion —(CnH2n-2)—stands for lower alkylene forming with Ph a six- or seven-membered ring, two of the ring carbon atoms thereof carry the groups Ar and R, salts, N-oxides, salts of N-oxides and quaternary ammonium compounds thereof.
Lednicer, et al., in J. Med. Chem. 10, 78 (1967) and in U.S. Pat. No. 3,274,213 refer to compounds of the formula
wherein R1 and R2 are selected from the class consisting of lower alkyl and lower alkyl linked together to form a 5 to 7 ring member saturated heterocyclic radical.
1. Kanapure, S. P.; Das, K. G.; Bhawal, B. M. Synth. Comm. 1984, 14,1205-1211.
2. Lexa, D.; Saveant, J. M.; Zickler, J. J. Amer. Chem. Soc. 1977, 99, 2786-2790.
3. Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203-205.
4. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J. Tet Lett. 1986, 27, 279-282.
5. McMurry, J. E.; Kees, K. L. J. Org. Chem. 1977, 42, 2655-2656.
This invention provides intermediate compounds which are useful for the preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. These compounds include: 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one; 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane; 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one; and 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene; and (4-Benzyloxy-phenyl)-{4-methoxy-2-[2-(2-phenyl-[1,3]dioxolan-2-yl)-ethyl]-phenyl}-methanone.
This invention also provides a method of preparing Cis-1-{4-[6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenoxy]ethyl}pyrrolidine which comprises the following steps:
1) 2-Bromo-5-methoxy-toluene is brominated to provide 1-bromo-2-bromomethyl-4-methoxybenzene;
2) The product of step 1 is used to alkylate benzoyl acetate ethyl ester followed by decarboxylation to provide 3-(2-bromo-5-methoxyphenyl)-1-phenyl-propan-1-one;
3) The product of step 2 is reacted with ethylene glycol to produce 2-[2-(2-bromo-5-methoxyphenyl)-ethyl]-2-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane;
4) The product of step 3 undergoes metal-halogen exchange with n-butyl lithium and is reacted with 4-benzyloxy benzonitrile to produce 2-[2-(2-(4-benzyloxybenzoyl)-5-methoxy phenyl)-ethyl]-2-phenyl-[1,3]-dioxolane which is subjected to acid hydrolysis of the 1,3 dioxolane to provide 3-[2-(4-benzyloxybenzoyl)-5-methoxyphenyl]-1-phenyl propan-1-one;
5) The product of step 4 is treated with titanium (III) chloride and zinc-copper couple to produce 4-(4-benzyloxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene;
6) The product of step 5 is hydrogenated and treated with triphenyl phosphine, DEAD and 1-(2-hydroxyethyl)pyrolidine to produce 1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)-ethyl}-pyrolidine.
which comprises reacting 2-[2-(2-bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane with butyl lithium followed by reaction with
This invention provides a new synthesis of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine as shown below.
Acronyms used in this description are defined as follows:
NBS | N-bromosuccinimide | ||
AIBN | 2,2′-Azobisisobutyronitrile | ||
TMSCl | Trimethyl chloro silane | ||
THF | tetrahydrofuran | ||
PPTS | pyridine p-toluene sulfonate | ||
DEAD | Diethyl azodicarboxylate | ||
DME | Dimethoxy ethane | ||
The term “protected phenol” includes optional benzyloxy groups substituted with alkoxy, nitro or halogen, and other acceptable alcohol protecting groups.
The synthesis begins with bromination1 of 2-bromo-5-methoxy-toluene to provide the benzyl bromide 1-Bromo-2-bromomethyl-4-methoxy-benzene. Alkylation of ethyl benzoylacetate2 with the benzyl bromide followed by decarboxylation leads to the ketone 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one, which is protected3 as the ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane. Metal-halogen exchange of ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane provides an aryl-lithium species, which adds readily to either 4-benzyloxy-benzoate or 4-benzoxy-benzontrile4 and furnishes the diketone 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one upon acidic work-up. The diketone undergoes a titanium mediated McMurry type coupling5 to provide the alkene 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene, which possesses the carbon framework of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine with all the functional groups in place. A palladium catalyzed hydrogenation achieves the reduction of the olefinic double bond and deprotection of the benzyl ether in one pot. The introduction of the N-ethyl-pyrrolidino side-chain is achieved under Mitsunobu conditions to afford 1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine, the key precursor to cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine. This compound is converted to cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol with HBr as described in U.S. Pat. No. 5,552,241.
1-Bromo-2-Bromomethyl-4-Methoxy-Benzene
Reference: Synthetic Communications, 1984, 1205-1211
To a solution of 2-bromo-5-methoxytoluene (50 g, 0.25 mol) in dichloroethane (375 ml), N-bromosuccinimide (48.8 g, 0.275 mol) and AIBN (1.36 g) were added and the reaction was refluxed for 4 h. The cooled solution was filtered and the solvent was evaporated to give a weight of 44.8 g crude 1-Bromo-2-bromomethyl-4-methoxy-benzene (64% yield).
This compound was used in next step without further purification.
3-(2-Bromo-5-Methoxy-Phenyl)1-Phenyl-Propan-1-One
Reference: JACS, 1977,2786
To sodium ethoxide (5.72 g, 84 mmol) in 50 ml of anhydrous ethanol was added 14.8 g (77 mmol) of ethyl benzoylacetate with stirring. The reaction mixture was then brought to a gentle reflux and 19.6 g (70 mmol) of 1-Bromo-2-bromomethyl-4-methoxy-benzene in 20 ml of ethanol was added over 20 min. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled, filtered and concentrated. The concentrated mixture was subjected to acid hydrolysis and decarboxylation by refluxing for overnight in a solution containing 40 ml of glacial acetic acid, 5 ml of concentrated sulfuric acid, and 10 ml of water. The reaction mixture was then neutralized with 10% NaOH and extracted with methylene chloride. The extracts were concentrated to give a weight of 19.43 g crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one (yield: 87%). This compound was used in next step without further purification.
2-[2-(2-Bromo-5-Methoxy-Phenyl)-Ethyl]-2-Phenyl-[1,3]Dioxolane
Reference: Synthesis, 1983,203
To a solution of crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one (19.43 g, 61 mmol) in dry ethylene glycol (300 ml) under a N2 atmosphere was added chlorotrimethylsilane (31 ml, 0.25 mol). The reaction was stirred at room temperature for 1 h. A 5% aqueous NaHCO3 (300 ml) was added. The mixture was extracted with diisopropyl ether, and the extracts were washed with brine. The combined ether extracts were dried with Na2SO4 and the solvent was removed under reduced pressure to produce a weight of 21.52 g crude 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane (yield: 97%).
4-Benzyloxy-Benzonitrile
Reference: Tetrahedron Lett. 1986, 279-282
To a solution of 4-cyanophenol (25 g, 0.21mol) and K2CO3 (138 g, 1 mol) in DMF (300 ml) was added benzyl chloride (27.91 g, 0.22 mol) in one portion. The resulting mixture was stirred at room temperature overnight. The suspension was filtered and the filtrate was poured into iced water. The resulting solid was collected to provide a weight of 43.5 g product (yield: 99%).
3-[2-(4-Benzyloxy-Benzoyl)-5-Methoxy-Phenyl]-1-Phenyl-Propan-1-One
A solution of 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane (0.9 g, 2.5 mmol) in 10 ml of dry THF was cooled to −78° C. and n-BuLi (2.5 M in hexane, 1 ml) was added dropwise. The solution was stirred at −78° C. for 2 h and 4-benzyloxy-benzonitrile (0.575 g, 2.75 mmol) in 2 ml of THF was added. The mixture was allowed to warm to room temperature and refluxed overnight. The solution was then quenched with sat. NH4Cl and the solvent was evaporated. A solution of the residue in 20 ml of wet acetone, 5 ml of H2O containing PPTS (188 mg, 0.75 mmol) was refluxed overnight. Regular workup and column purification afforded an unoptimized weight of 0.8 g 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one.
(4-Benzyloxy-Phenyl)-7-Methoxy-3-Phenyl-1,2-Dihydro-Naphthalene
Reference: JOC, 1977, 2656
TiCl3 (2.062 g, 13 mmol) and Zn—Cu couple (2.02 g, 30.8 mmol) were placed in a 200 ml round bottom flask under N2. Anhydrous dimethoxyethane (40 ml) was added and the mixture was refluxed for 1 h.
Note: The Zn—Cu couple is prepared by adding zinc dust (9.8 g, 150 mmol) to 40 ml of deoxygenated water, purging the slurry with N2 gas for 15 min, and than adding CuSO4 (0.75 g, 4.7 mmol). The black slurry was filtered under N2, washed with deoxygenated H2O, acetone, ether, and then stored under N2.
3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one (540 mg, 1.2 mmol) in 80 ml of DME was added to the refluxing slurry and the resulting mixture was refluxed for 15 min. The suspension was filtered and the solvent was evaporated to give a weight of 0.45 g 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene (yield: 90%, structure was confirmed by X-ray).
1-{2-[4-(6-Methoxy-2-Phenyl-1,2,3,4-Tetrahydro-Naphthalen-1-yl)-Ethyl}-Pyrrolidine
4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene (0.45 g, 1.08 mmol) was dissolved in a mixture of EtOH (15 ml) in a Paar bottle. Pd(OH)2 (0.3 g) in 2 ml of H2O was added and the mixture was shaken under H2 (50 psi) at room temperature. The solution was filtered and treated with same equivalent of triphenylphosphine, DEAD and 1-(2-hydroxyethyl)pyrrolidine. Normal workup gave 1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl}-pyrrolidine.
Claims (1)
1. A compound selected from the group consisting of 3-(2-Bromo-5-methoxy-phenyl)1-phenyl-propan-1-one; 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane; 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one; 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene; and (4-Benzyloxy-phenyl)-{4-methoxy-2-[2-(2-phenyl-[1,3]dioxolan-2-yl)-ethyl]-phenyl}-methanone.
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US09/794,382 US6323345B1 (en) | 1999-05-24 | 2001-02-27 | Process for Cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine |
US09/974,309 US6395911B1 (en) | 1999-05-24 | 2001-10-09 | Process for cis-1{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy] ethyl}pyrrolidine |
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US6395911B1 (en) * | 1999-05-24 | 2002-05-28 | Pfizer Inc. | Process for cis-1{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy] ethyl}pyrrolidine |
US20030212122A1 (en) * | 2002-03-28 | 2003-11-13 | Mclaughlin Robert W. | Purified racemic lasofoxifene and purified lasofoxifene D-tartrate and a method for effective purification of racemic lasofoxifene |
US20070110800A1 (en) * | 2002-07-10 | 2007-05-17 | Pfizer Inc | Pharmaceutical composition having uniform drug distribution and potency |
US10258604B2 (en) | 2016-10-11 | 2019-04-16 | Duke University | Lasofoxifene treatment of breast cancer |
US11497730B2 (en) | 2018-04-10 | 2022-11-15 | Duke University | Lasofoxifene treatment of breast cancer |
US12023321B2 (en) | 2021-11-18 | 2024-07-02 | Sermonix Pharmaceuticals, Inc. | Lasofoxifene treatment of aromatase-resistant ER+cancer |
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JP5212931B2 (en) * | 2006-01-26 | 2013-06-19 | 学校法人東京理科大学 | Method for producing lasofoxifene and its analogs |
CZ2007373A3 (en) * | 2007-05-29 | 2008-12-10 | Zentiva, A. S | Process for preparing lasofoxifene |
CN102424661A (en) * | 2011-10-21 | 2012-04-25 | 南开大学 | Synthetic method of azo pigment hapten and artificial antigen |
CN103113323B (en) * | 2013-02-05 | 2015-11-11 | 南京华威医药科技开发有限公司 | The preparation method of Lasofoxifene tartrate intermediate |
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US7358374B2 (en) | 2002-03-28 | 2008-04-15 | Pfizer Inc. | Purified racemic lasofoxifene and purified lasofoxifene D-tartrate and a method for effective purification of racemic lasofoxifene |
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